The present invention relates to a particularly advantageous process for preparing N-aryl-N'-alkyl-piperazines from anilines and diethanolamines.
N-aryl-N'-alkyl-piperazines are important intermediates for preparing pharmaceutically active compounds for diverse indications. Triazole-4,3-a!-pyridine derivatives having sedative, hypotensive and analgesic action can be obtained, for example, from N-aryl-N'-halogenopropyl-piperazines by reaction with s-triazolo-4,3-a!-pyridin-3-one (see U.S. Pat. No. 3,381,009).
A plurality of processes for preparing N-aryl-N'-alkyl-piperazines have been disclosed; however, all of these are unsatisfactory.
According to GB patent specification 889 223 an aniline derivative is initially reacted with ethylene oxide to give the corresponding N-bishydroxyethyl-aniline whose OH groups are subsequently replaced by chlorine, and the resulting N-bischloroethyl-aniline is finally reacted with ethanolamine with formation of a piperazine ring. This process comprises a number of steps and is therefore complicated.
GB patent specification 948 767 and U.S. Pat. No. 3,326,916 describe the reaction of m-trifluoromethylaniline with diethanolamine/hydrogen bromide or bis-2-chloroethylamine to give N-aryl-N'-unsubstituted piperazines. An N'-alkyl substituent has to be introduced separately. This process also comprises several steps and is therefore complicated. In addition, bis-2-chloroethylamine and diethanolamine/hydrogen bromide can only be handled if certain industrial hygiene requirements are met.
Finally, it is known to prepare N-aryl-N'-hydroxyethyl-piperazine by condensation of triethanolamine with aniline in the presence of sulfuric acid, the reaction being carried out by boiling at reflux, i.e. at atmospheric pressure (see J.A.C.S. 58, 379(1936)). The yields that can be obtained are not mentioned. A repetition of the experiment using n-trifluoromethylaniline instead of aniline showed that the yields which can be obtained are low and the reaction times required are long (see Comparative Example).
There is therefore still a demand for a simple process for preparing N-aryl-N'-alkyl-piperazines in good yields and short reaction times.